DESCRIPTION: (Applicant's Abstract) The long-term objective of this research is to improve clinical management of severe and persistent cancer-related pain that is not adequately relieved by the use of opioid analgesics alone. Tricyclic antidepressants (TCA) are frequently added to an existing regimen of opioid analgesics in an attempt to improve pain control. While uncontrolled clinical studies have shown that the adjunctive use of TCA results in further pain relief in some patients, aggravation of pre-existing opioid-induced side effects and/or the appearance of new side effects were also noted. To fully assess the clinical advantage of co-analgesic therapy with TCA, we need to compare the gain in analgesia relative to the added burden in side effects. With the advent of selective serotonin reuptake inhibitors (SSRIs) which exhibit much less troublesome side effects than the TCA, considerable interest exists as to their potential as co-analgesics. A recent clinical study suggested that subacute administration of fluoxetine may antagonize the analgesic effect of a mu-opioid morphine. Hence, there is a need to further evaluate the pharmacodynamic interaction between SSRIs and opioids. This proposal outlines a placebo-controlled, laboratory-based trial in human volunteers to compare the effects of acute, subacute and chronic administration of low doses of desipramine (a TCA and a norepinephrine or NE reuptake inhibitor), paroxetine (an SSRI) and venlafaxine (a dual serotonin or 5-HT and NE reuptake inhibitor) on the analgesia and side effects profiles (i.e., therapeutic ratios) of morphine. The experimental pain paradigm consists of cutaneous electrical stimulation and thermal sensory testing. Side effect measurements include subjective and observer ratings of sedation, cognitive assessment and respiratory depression. The effect measures will be related to both plasma drug-metabolite concentration and in vitro noradrenergic and serotonergic functions of platelets isolated from the subjects. A major goal of this repeated-measures study is to test the hypothesis that neuronal adaptation results in a change in the interactive effects of the antidepressant-opioid combination over the first few weeks of therapy and determines the eventual efficacy of the antidepressant as a co-analgesic or promoter of opioid analgesia. Specifically, we hypothesize that subacute treatment with desipramine leads to potentiation of morphine induced analgesia and, upon longer treatment, results in a loss of potentiating effect due to sub-sensitization of alpha-adrenergic receptor function. In contrast, subacute treatment with paroxetine results in antanalgesic effect and reverses to a potentiating effect upon chronic treatment due to adaptation of serotonergic neurons. We further hypothesize that venlafaxine maintains a potentiating effect on opioid analgesia over time due to its combined actions on NE and 5-HT reuptake.